A growing body of research supports genetic influences on brain structure and function. Much of this work has been done in healthy adults. In parallel, there has been substantial investigation into genetic factors that may predispose individuals to the development of depression. Despite our growing understanding of genetic factors that may affect brain structure and function in healthy adults, there is limited research investigating whether these polymorphisms have a differential effect in depressed adults. The present study will examine the influence two genetic polymorphisms on brain structure and neurocognitive function. These polymorphisms have been implicated in alterations in brain structure and function in healthy individuals and may serve as susceptibility genes for depression. Hypotheses: The short allele of the serotonin transporter promoter region and the catechol-O-methyltransferase val158met polymorphism will each be associated with alterations in brain structure and neurocognitive function in a cohort of 120 adults with recurrent Major Depressive Disorder and 120 adults with no psychiatric illness. As an exploratory hypothesis, we will examine genetic influences on brain structure and function that may be specific to the depressed cohort. Methods: This is a cross-sectional study wherein subjects will complete brain magnetic resonance imaging, neurocognitive testing, and provide a serum genetic sample. Image analysis and neurocognitive testing will focus on regions shown to be associated with these genetic polymorphisms: the amygdala, hippocampus, and dorsolateral prefrontal cortex. Both volumetric and diffusion tensor image analysis methods will be used. Relevance: This study addresses NIMH's mission of better understanding the underlying pathophysiology of depression, using translational research to incorporate methods across scientific disciplines. It is relevant to public health concerns given that depression is a common problem and its pathophysiological basis is poorly understood. The project will provide information on how genetic factors affect the brain and how this may differ for individuals with recurrent depression. A better identification of these differences will further our understanding of the pathophysiology of depression, allowing the development of more focused treatments.Project Narrative: This project will examine two genes, one involved with serotonin and the other with dopamine, and their effect on brain structure and function on people with and without depression. A better understanding of how genes affect the brain is critical as we better understand depression, a serious illness which results in significant disability and mortality. This study will advance our understanding of how genes affect the brain, which in turn will provide important information on the causes of depression.